The major objectives of this proposal are to continue investigations of our recent findings that in vitro culture of rat islets at 24 degrees C for 7 days prior to transplantation, in conjunction with a single injection of anti-rat lymphocyte serum into the diabetic recipients, results in marked prolongation of allograft survival of islets transplanted across a major histocompatibility barrier. The mechanism of prolonging islet allograft survival appears to be due to alterations of leucocytes by this procedure since injection of peritoneal exudate cells from the donor strain initiates rejection of successful islet allografts 100-200 days after transplantation. The specific objectives are to continue studies on the effect of dispersion cultures and islet cells with subsequent reaggregation into islets to assist in eliminating passenger leucocytes; continue studies on the use of the allograft model to attempt to prolong survival of islet xenografts (hamster to rat); continue studies on the identification specific passenger cell type or types required for initiation of islet allograft rejection; determine the effect of implantation site (muscle and liver via portal vein or direct implantation) on allograft survival; attempt to improve the collagenase technique for isolation of islets from compact pancreases (beef, pig and human); after establishing the optimum allograft model long-term studies will be initiated on the metabolic and hormonal status of recipients bearing rat islet allografts.